It was recognised early in this century that feeding experimental animals an antigen they had previously not encountered elicited transient symptoms of immediate hypersensitivity, which waned with continued food antigen exposure, to be replaced by a state of antigen-specific unresponsiveness. The phenomenon is now known as Oral Tolerance, and has been shown to be preferentially directed against IgE-mediated immediate hypersensitivity responses and delayed-type hypersensitivity responses (1). This form of tolerance can be transferred from animal to animal by T-cells secreting TH-1-like cytokines (2,3), and allergen specific T-cells secreting such cytokines develop rapidly in the mesenteric lymph nodes during allergen feeding.(10,12)
The inventor was the first to recognise the equivalent phenomenon in the respiratory tract, and has been investigating the underlying mechanisms since the early 1980s (4,5). The essential elements are identical: repeated inhalation of antigen aerosols elicits an initially heterogenous immune response which includes a component of TH-2-dependent IgE production, but the latter eventually wanes in the face of repeated antigenic challenge, leaving only vestiges of specific IgG and IgA production. Animals passively exposed to antigen aerosols in this fashion are unable to mount subsequent IgE responses to the same antigen for the remainder of their lives, regardless of the route or intensity of challenge. As is the case with antigen feeding, the "tolerance" resulting from antigen inhalation is expressed preferentially against IgE and delayed-type hypersensitivity, and is mediated by T-cells, including a population expressing CD8, which secrete TH-1-like cytokines(6), Additionally, the option for this form of "tolerance" induction appears open to the immune system only at or around the time of initial allergen exposure--presensitised animals with stable on-going IgE responses are not "desensitised" by aerosol exposure(4,5).
These processes exhibit two further important features in common in experimental animals. Firstly, sensitivity to tolerance induction is genetically determined, and high sensitivity is co-inherited with the low-IgE-responder-phenotype. Operationally, this manifests as a requirement for up to 10.sup.3 to 10.sup.4 -fold more intense allergen exposure to successfully tolerise high-IgE-responder rats and mice, compared to their low-responder counterparts. However, it is clear that both high and low responders can ultimately be tolerised by either route, and the inherent sluggishness of these mechanisms in the high-IgE-responders can be overcome by applying more intense allergen stimulation(4,5).
Secondly, the process functions poorly in the pre-weaning period(7), to the extent that allergen exposure in the very early phase of infancy can prime for subsequent pathogenic T-cell reactivity, as opposed to inducing protective tolerance: this is consistent with the existence of an early "window" of high risk for allergic sensitization, presumably due to delayed postnatal maturation of one or more key elements of mucosal immune function which are rate-limiting in the tolerance induction process(7).
It is not clear to what extent mucosal allergen exposure via the gastrointestinal tract can suppress ongoing TH-2 responses in IgE-positive high-responder animals, but recent work employing intranasally administered allergen peptides encourages further pursuit of this approach in the context of desensitisation.
Initial exposure of humans to ubiquitous environmental allergens occurs during infancy or early childhood, and the notion that many of the triggers for allergic disease in the adult are set during childhood is attracting increasing attention. In this context, there is a growing consensus, based upon an expanding paediatric sero-epidemiological literature, that high-level allergen. exposure during the first few months of life predisposes to allergic sensitisation (7), which manifests in later childhood as TH-2-like reactivity. This implies that, as in experimental animals, transient maturational defect(s) in aspects of immune function which are important for efficient "selection" for TH-1 reactivity to allergens encountered at mucosal surfaces may also be common in newborn humans.
The present inventor has now recognized that the key element of the relevant human literature, however, is the characteristic biphasic nature of IgE responses to individual food and inhalant allergens which commonly occur during early childhood.
Thus, both normal children and those with a family history of atopic responses typically develop serum IgE antibody responses against common food allergens during the first year of life, their magnitude and duration reflecting IgE-responder-phenotype(8). A comparable pattern is evident for IgE responses to inhalant allergens(8) (FIG. 1); however, the latter commence later in infancy, and take considerably longer to switch off ("tolerise") in the non-atopics. Furthermore, a much higher proportion of potential atopics maintain their serum IgE reactivity to inhalant allergens into later childhood than they do for food allergens(8).
These differences in the kinetics and overall efficiency of "tolerance" induction to inhalant versus dietary antigens may derive directly from the differing levels of antigen exposure in the two organs: as T-cell subset selection is "antigen driven", the less intense stimulation provided via low-level respiratory tract exposure may be expected to result in a slower and ultimately less efficient process.
It is known that the magnitude and duration of IgE responses to parenteral antigenic challenge in experimental animals is regulated by competing signals from CD4.sup.+ T-cell subsets. In particular T-helper-2 (TH-2) cells, which secrete interleukin-4 and interleukin-5, promote IgE-B-cell switching, and TH-1 cells, which secrete interleukin-2 and interferon-.gamma., inhibit TH-2 clonal expansion and hence limit the IgE response (9) The present inventor's review of a variety of data obtained using in vitro experimental systems employing human peripheral blood T- and B-cells indicates that an identical mechanism exists in man(10), and this view is reinforced by the clear demonstration that both atopic and IgE-negative normal adults contain T-cells in peripheral blood which are reactive to the major inhalant allergens: in the atopic individuals, these cells appear to be predominantly of the TH-2 type, whereas in non-atopic individuals they appear to be mainly TH-1 (11) Considerable debate surrounds the precise classification of these human T-cell subsets relative to their murine counterparts, as respective cytokine patterns are not identical in the two species; accordingly, current opinion favours their classification in man as TH1-"like" and TH-2-"like" respectively.
Thus we suggest that in the non-atopic adult, each exposure to an environmental allergen would elicit a burst of TH-1-like cytokine release at sites of allergen presentation to the T-cell system, which would "protect" against the emergence of potentially pathogenic TH-2-like reactivity; each exposure event would additionally serve to consolidate host-protective TH-1-like "memory".